Pyramidal cell dendrites combine excitatory postsynaptic potential from tens of thousands of synapses spread across hundreds of microns of membrane. These voltage transients are then propagated to the soma. Until recently, it has been hypothesized that the integration and transfer of synaptic inputs involved only passive properties of dendrites. However, recent work on the properties of pyramidal cell dendrites has shown that the somatic response to input to the apical dendrites is modulated by voltage-dependent conductances in the soma and dendrite and thus is not passive. This observation raises the possibility that summation of synaptic responses is influenced by dendritic non-linearities, and that the summation will be modified by changes in the properties of postsynaptic voltage dependent channels. Modeling studies have suggested that dendritic non-linearities introduced by the addition of voltage dependent sodium and calcium channels may provide a mechanism whereby pyramidal cell dendrites sum synaptic inputs super-linearly, allowing dendritic branches to perform complex computions or to detect coincident inputs. The central hypothesis of the proposal is that conductances underlying the active propagation of perforant path (PP) synaptic input are modulated by: i) changes in membrane voltage, ii) modulatory inputs. PP is the output of the entorhinal cortex and a major source of ipsilateral extrinsic afferents to the dentate gyrus granule cells, and to hippocampal pyramidal cells in areas CA1 and CA3. Thus, the PP input plays a central role in the neural coding and integration in cognitive functions subserved by the hippocampal formation, i.e., memory and learning. The central hypothesis will be tested with whole-cell recordings, anatomical labeling, electrical stimulation and flash photolysis of caged compounds. These investigations will address the following Specific Aims: 1) To determine the properties and mechanisms of active summation of PP EPSPs with other voltage changes in CA3 pyramidal cells. We will investigate how PP EPSPs are affected by changes in membrane potential. 2) To determine the mechanisms of the actions of neuromodulators on the boosting of PP EPSP. The postsynaptic actions of two neuromodulators known to play important roles in hippocampal function, acetylcholine (Ach) and norepinephrine (NE), will be investigated. 3) To determine the properties and mechanisms of active summation of PP EPSPs in CA3 interneurons. We will investigate the characteristics of PP input to these interneurons